Lewis Acid Mediated Reactions of Cyclopropyl Aryl Ketones with r-Ketoesters: Facile Preparation of 5,6-Dihydropyran-2-ones Yong-Hua Yang and Min Shi* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
[email protected] Received August 28, 2005
A new general method for the synthesis of 5,6-dihydropyran-2-ones from cyclopropyl aryl ketones (monoactivated cyclopropanes) and R-ketoesters in good to excellent yields has been developed. The process involves a cascade of reactions, including a nucleophilic ring-opening reaction of monoactivated cyclopropane by H2O, Lewis acid mediated transesterification, and an aldol type reaction.
Introduction Cyclopropane derivatives, as versatile building blocks, have been more than laboratory curiosities for quite some time.1 Electron-donating or -accepting substituents are generally involved in the activation of strained threemembered rings, as they make polar processes more favorable. However, cyclopropanes involved in synthetically useful reactions frequently contain two activating groups.2 Ring-opening reactions of monoactivated cyclopropane derivatives are generally sluggish because of their low reactivities. So far the only reported examples have required severe conditions assisted either by strong nucleophiles such as the iodide anion3 and strong Lewis acids such as TiCl44 or by the β-effect of the silicon atom of a trimethylsilyl group.5 More recently, a Bu3SnHmediated free-radical process and a SmI2-promoted electron-transfer process have been also reported with this transformation.6 Therefore, it is desirable to develop methods for ring-opening reactions of simple monoactivated cyclopropane derivatives under mild conditions. (1) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Paquette, L. A. Chem. Rev. 1986, 86, 733. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (d) de Meijere, A.; Wessjohann, L. Synlett 1990, 20. (e) Kulinkovich, O. G. Russ. Chem. Rev. 1993, 62, 839. (f) Kulinkovich, O. G. Pol. J. Chem. 1997, 849. (g) Wenkert, E. Acc. Chem. Res. 1980, 13, 27. (h) Wenkert, E. Heterocycles 1980, 14, 1703. (i) Seebach, D. Angew. Chem. 1979, 91, 259; Angew. Chem., Int. Ed. 1979, 18, 239. (j) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603. (2) (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (b) Avilov, D. V.; Malusare, M. G.; Arslancan, E.; Dittmer, D. C. Org. Lett. 2004, 6, 2225.
SCHEME 1. Reaction of Cyclopropyl Aryl Ketones with Arylaldehydes Promoted by the Lewis Acid TMSOTf.
Recently, we reported the ring-opening reaction of cyclopropyl aryl ketones 1 with arylaldehydes to afford 2-(2-hydroxyethyl)-1,3-diarylpropenones 2 in the presence of a Lewis acid (Scheme 1).7 We envisioned that this (3) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987. (b) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (c) Smith, A. B., III; Scarborough, R. M. Tetrahedron Lett. 1978, 19, 1649. (d) Ogoshi, H.; Setsune, J.-I.; Yoshida, Z.-I. J. Organomet. Chem. 1980, 185, 95. (e) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.; Toi, H.; Aoyama, Y. Organometallics 1987, 6, 2175. (f) Ru Hwu, J. Chem. Commun. 1985, 452. (g) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (h) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333. (i) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312. (j) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028. (k) Scott, M. E.; Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309. (4) (a) Lim, Y.-H.; McGee, K. F., Jr.; Sieburth, S. M. J Org. Chem. 2002, 67, 6535. (b) Yates, P.; Helferty, H.; Mahier, P. Can. J. Chem. 1983, 61, 78. (c) Demuth, M.; Raghavan, P. R. Helv. Chim. Acta 1979, 62, 2338. (5) Yadav, V. K.; Balamurugan, R. Org. Lett. 2003, 5, 4281. (6) (a) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 5248. (b) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 9159. (c) Batey, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6649. (d) Batey, R. A.; Harling, J. D.; Motherwell, W. B. Tetrahedron 1996, 52, 11421. (7) Shi, M.; Yang, Y.-H.; Xu, B. Tetrahedron 2005, 61, 1893. 10.1021/jo051815z CCC: $30.25 © 2005 American Chemical Society
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Published on Web 10/27/2005
Facile Preparation of 5,6-Dihydropyran-2-ones SCHEME 2. Design of a Cascade Process for the Preparation of 5,6-Dihydropyran-2-ones
TABLE 1. Reactions of Cyclopropyl Phenyl Ketone 1a
with r-Ketoester 3a Mediated by Various Acids in DCEa
entry
process included a ring-opening reaction of the cyclopropane moiety by nucleophilic attack of ambient H2O and a subsequent aldol type reaction in the presence of a Lewis acid. A natural extension of this work is to explore the possibility of replacing the arylaldehyde with other carbonyl-containing compounds. The primary hydroxyl group in product 2 inspired us to determine whether a tandem reaction process could be applied to the preparation of 5,6-dihydropyran-2-one compounds (5) if the subsequent transesterification reaction takes place. It is well-known that 5,6-dihydropyran-2-ones are an important class of compounds because they are skeletal motifs in many natural products that possess important biological activities.8 Therefore, we selected R-ketoesters 3 for use in this reaction to replace the arylaldehyde on the basis of this hypothesis (Scheme 2). Results and Discussion To determine whether such a reaction cascade is possible, we examined the reaction of cyclopropyl phenyl ketone (1a) with methyl 2-oxo-phenylacetate (3a) mediated by a variety of Lewis acids. As can be seen from Table 1, 4-benzoyl-3-phenyl-5,6-dihydropyran-2-one (5a) was indeed obtained in the presence of 0.5 equiv of the Lewis acid Zr(OTf)4 or TMSOTf, or the Brønsted acid TfOH in 66, 64, and 52% yields, respectively, in 1,2dichloroethane (DCE) at 60 °C with some recovered starting materials within 10 h (Table 1, entries 1-3). The Lewis acids BF3‚OEt2, TiCl4, and SnCl4 and Brønsted acid p-toluenesulfonic acid exhibited comparatively much lower catalytic abilities in this reaction, with the recovery of most of the starting materials. Other metal triflates, such as Zn(OTf)2 and Yb(OTf)3, cannot mediate this reaction under the same reaction conditions. When the amount of the Lewis acid TMSOTf or Zr(OTf)4, or the Brønsted acid TfOH used was increased to 1.0 equiv, the yields of 5a were enhanced to 89, 66, and 72%, respectively (Table 1, entries 4-6), with Lewis acid TMSOTf being the best promoter for this reaction. We also examined various solvents in this reaction using TMSOTf as the Lewis acid, and the results are summarized in Table 2. We found that DCE is the best (8) (a) Takaya, Y.; Kikuchi, H.; Terui, Y.; Komiya, J.; Furukawa, K.-I.; Seya, K.; Motomura, S.; Ito, A.; Oshima, Y. J. Org. Chem. 2000, 65, 985. (b) Giorgio, E.; Maddau, L.; Spanu, E.; Evidente, A.; Rosini, C. J. Org. Chem. 2005, 70, 7. (c) Akiyama, K.; Yamamoto, S.; Fujimoto, H.; Ishibashi, M. Tetrahedron 2005, 61, 1827. (d) Chandrasekhar, S.; Narsihmulu, C.; Shameem Sultama, S.; Srinivasa Reddy, M. Tetrahedron Lett. 2004, 45, 9299. (e) Iqbal Choudhary, M.; Yousuf, S.; Ahmad Nawaz, S.; Ahmed, S.; Atta-Ur-Rahman Chem. Pharm. Bull. 2004, 52, 1358.
1 2 3 4 5 6
Lewis acid (equiv)
yieldb of 5a (%)
Zr(OTf)4 (0.5) TfOH (0.5) TMSOTf (0.5) Zr(OTf)4 (1.0) TfOH (1.0) TMSOTf (1.0)
66 64 52 66 72 89
a All reactions were performed at 60 °C for 10 h on a 0.3 mmol scale with the use of 1a and 3a. See Supporting Information for details. b Isolated yields.
TABLE 2. Solvent Effects in the Reaction of
Cyclopropyl Phenyl Ketone 1a with r-Ketoester 3a Mediated by TMSOTf (1.0 equiv)
entry
solvent
T (°C)
yielda of 5a (%)
1 2 3 4
DCE THF MeCN toluene
60 60 60 100
89 22 0 trace
a
Isolated yields.
solvent for this reaction. As for THF and MeCN, the reactions became sluggish, and most of starting materials were recovered, presumably because of the coordination of THF and MeCN to the silicon atom in Lewis acid TMSOTf (Table 2, entries 2 and 3). At a higher temperature in toluene (100 °C), the reaction solution was deep colored and only a trace amount of 5a was formed, which indicated that high reaction temperatures do not favor the reaction (Table 2, entry 4). Next, the scope of this new and efficient synthetic protocol for the construction of 5,6-dihydropyran-2-ones was investigated by employing a variety of cyclopropyl aryl ketones and R-ketoesters under the optimized conditions. As shown in Table 3, starting from cyclopropyl phenyl ketone (1a) and various R-ketoesters, the corresponding 5,6-dihydropyran-2-ones 5a-h were obtained in moderate to excellent yields (Table 3, entries 1-8). From the reactions of 1a with various aryl R-ketoesters, electronic effects were clearly observed. In general, aryl R-ketoesters having no substituents or electron-withdrawing groups on the aromatic ring were more reactive, and afforded the corresponding products 5 in better yields (Table 3, entries 1 and 4). For aryl R-ketoesters 3b and 3c, which bear an electron-donating substituent (methyl or methoxyl group) on the aromatic ring, the corresponding products 5 were obtained in lower yields under the same conditions (Table 3, entries 2 and 3). On the other hand, ethyl glyoxalate (3e) showed a high reactivity in this reaction, and afforded the corresponding product 5e in 94% yield because of the high electrophilicity of the aldehyde moiety in 3e (Table 3, entry 5). As for aliphatic J. Org. Chem, Vol. 70, No. 24, 2005 10083
Yang and Shi TABLE 3. Reactions of Cyclopropyl Aryl Ketones 1a-f with Various r-Ketoesters under Optimized Conditions
entry
R1
R2/R3
1 2 3 4 5 6 7 8 9 10 11 12 13
1a, C6H5 1a, C6H5 1a, C6H5 1a, C6H5 1a, C6H5 1a, C6H5 1a, C6H5 1a, C6H5 1b, p-FC6H4 1c, p-MeC6H4 1d, o,o-Me2C6H3 1e, p-MeOC6H4 1f, thiophen-2-yl
3a, C6H5/Me 3b, p-MeC6H4/Me 3c, p-MeOC6H4/Et 3d, p-ClC6H4/Et 3e, H/Et 3f, Me/Et 3g, hexyl/Et 3h, cyclohexyl/Et 3f, Me/Et 3f, Me/Et 3f, Me/Et 3f, Me/Et 3f, Me/Et
a
SCHEME 3. Reaction of 1a with 3a Mediated by TMSOTf in the Presence of 4 Å MS (100 mg)
yielda of 5 (%) 5a, 89 5b, 60 5c, 50 5d, 87 5e, 94 5f, 97 5g, 40 5h, 35
SCHEME 4. Reaction of 6a with 3a in the Presence of TMSOTf
5j, 97 5k, 92 5l, 72b 5m, 80b
Isolated yields. b The reaction time was prolonged to 2 days.
R-ketoesters, the reaction of ethyl pyruvate (3f) with 1a proceeded smoothly to afford 5f in 97% yield (Table 3, entry 6). However, when aliphatic R-ketoesters having a larger aliphatic group were utilized in this reaction, such as ethyl 2-oxo-octanoate (3g) and ethyl cyclohexyl-oxoacetate (3h), the yields of the corresponding products 5g and 5h abruptly decreased, presumably because of their steric bulkiness (Table 3, entries 7 and 8). Furthermore, we also examined the reactions of a variety of cyclopropyl aryl ketones with ethyl pyruvate 3f under these optimized conditions (Table 3, entries 9-13). A series of 4-substituted 3-methyl-5,6-dihydropyran-2-ones were prepared in good to excellent yields. Similar electronic effects were also observed as illustrated in Table 3. For cyclopropyl aryl ketones bearing an electron-rich aryl group, such as cyclopropyl 4-methoxyphenyl ketone (1e) and thiophene-derived substrate 1f, a prolonged reaction time (2 days) was required, and the corresponding products 5l and 5m were obtained in 72 and 80% yields, respectively (Table 3, entries 12 and 13). The structures of all products were determined by NMR spectroscopic data, microanalyses, and HRMS (see the Supporting Information). To understand the reaction mechanism for the formation of 5,6-dihydropyran-2-ones 5, we introduced 4 Å molecular sieves (100 mg for 0.3 mmol of substrate) into the reaction system to eliminate the ambient moisture. As a consequence, the reaction became sluggish, and gave only a trace of the desired product 5a after 1 day at 60 °C in the presence of TMSOTf (Scheme 3). This indicates that H2O probably plays a key role in the reaction mechanism. Moreover, we examined the effect of the amount of H2O on the reaction by adding of 1.0, 2.0, or 5.0 equiv of H2O into the reaction system. These control experiments showed that 1.0 equiv of H2O did not clearly affect the reaction, giving 5a in 88% yield under identical conditions. When the amount of H2O was increased to 2.0 or 5.0 equiv, the reaction turned out to be sluggish, giving 5a in 60 and 37% yields, respectively, along with some recovered starting materials, when performed 10084 J. Org. Chem., Vol. 70, No. 24, 2005
SCHEME 5. Proposed Mechanism of the Reaction of Cyclopropyl Aryl Ketone with r-Ketoester Mediated by Lewis Acid
under identical conditions. Therefore, we believe that an excess of H2O in the reaction system does not favor the reaction. Additionally, we prepared 4-hydroxy-1-phenylbutan1-one (6a) from the reaction of 1a with H2O in the presence of Lewis acid TMSOTf. We confirmed that 6a can react with methyl oxo-phenylacetate (3a) smoothly to give 5a in 85% yield within 5 h (Scheme 4). On the basis of the above results, a plausible reaction mechanism is proposed in Scheme 5. In the presence of a Lewis acid, cyclopropyl aryl ketone 1 reacts with ambient H2O to give the corresponding adduct 4-hydroxy1-arylbutan-1-one 6. This is consistent with the electronic effects observed in Table 3 (entries 6 and 9-13) because substrates 1, which are electrophiles and bear an electronwithdrawing group on the benzene ring, showed higher reactivities than those of electron-rich substrates, and gave the corresponding products 5 in higher yields. Thus, formed 6 reacts with the R-ketoester to produce another R-ketoester intermediate B through an intermolecular transesterification reaction and the release of an alcohol
Facile Preparation of 5,6-Dihydropyran-2-ones TABLE 4. Reaction of 1a with r-Ketoacetic Acid Catalyzed by TfOH
entry
catalyst
R
time (days)
yielda of 5 (%)
1 2 3
none TfOH (20 mol %) TfOH (20 mol %)
7a, Me 7a, Me 7b, C6H5
3 3 1
5e, trace 5e, 90 5a, 76
a
cyclopropanes by H2O, followed by a transesterification reaction and an aldol type reaction mediated by a Lewis acid to provide an efficient synthetic protocol for the preparation of 5,6-dihydropyran-2-ones. When an R-ketoacetic acid was subjected to the reaction instead of an R-ketoester, the corresponding 5,6-dihydropyran-2-one could be obtained in good yield with 20 mol % TfOH. Further work directed at elucidation of the detailed reaction mechanism and application of this procedure to the synthesis of R,β-unsaturated δ-lactone-containing natural products is currently in progress.
Isolated yields.
Experimental Section molecule. The product 5,6-dihydropyran-2-one 5 is formed through an intramolecular aldol type reaction from intermediate B along with the regeneration of 1 equiv of H2O (aldol type reaction), which can initiate the next reaction cycle. The mechanism is also consistent with the electronic effects observed in these reactions shown in Table 3 (entries 1-4) because R-ketoesters having electronwithdrawing groups on the benzene ring showed higher reactivities than those of R-ketoesters bearing electronrich groups on the benzene ring in the aldol type reaction, and gave the corresponding products 5 in higher yields. Overall, this process is a cascade of a nucleophilic ringopening reaction of the monoactivated cyclopropane by H2O, a transesterification reaction, and an aldol type reaction in the presence of Lewis acid. The Lewis and Brønsted acid-promoted reactions indicated that the construction of 5,6-dihydropyran-2-ones might proceed via a self-catalyzed process when an R-ketoacetic acid (7) was used instead of an R-ketoester. Unfortunately, only a trace amount of product was obtained from a reaction of 1a with pyruvic acid (7a) kept at 60 °C for 3 days in DCE (Table 4, entry 1). However, when 20 mol % TfOH was added, the reaction proceeded smoothly to give 5,6-dihydropyran-2-ones 5a and 5e in good yields (Table 4, entries 2 and 3). Conclusion In conclusion, we have developed a cascade process involving the ring-opening reaction of monoactivated
General Procedure for the Preparation of 5,6-Dihydropyran-2-one from Cyclopropyl Aryl Ketone with r-Ketoester. Under an argon atmosphere,the mixtures of cyclopropyl phenyl ketone 1a (0.3 mmol), R-ketoester 3 (0.3 mmol), and TMSOTf (0.3 mmol) were dissolved in 1,2-dichloroethane (DCE, 3 mL), and the reaction mixtures were heated to 60 °C for the necessary time. The reaction solution was cooled to room temperature, and was then quenched by addition of aqueous NaHCO3 solution. The reaction mixture was extracted by dichloromethane (3 × 15 mL), and dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to give the corresponding 5,6-dihydropyran-2-one product 5a as a white solid (yield: 89%, 74 mg).
Acknowledgment. We thank Dr. Wen Zhang for helpful discussion and offering some R-ketoesters. We also thank the State Key Project of Basic Research (Project 973, G2000048007), Shanghai Municipal Committee of Science and Technology, and the National Natural Science Foundation of China for financial support (20472096, 203900502, and 20272069). Supporting Information Available: The spectroscopic data of the compounds shown in Table 3 and the detailed description of experimental procedures. This material is available free of charge via the Internet at http://pubs.acs.org. JO051815Z
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